Advances in the variations and biomedical applications of stimuli-responsive nanodrug delivery systems.

Chemotherapy is an important cancer treatment modality, but the clinical utility of chemotherapeutics is limited by their toxic side effects, inadequate distribution and insufficient intracellular concentrations. Nanodrug delivery systems (NDDSs) have shown significant advantages in cancer diagnosis and treatment. Variable NDDSs that respond to endogenous and exogenous triggers have attracted much research interest. Here, we summarized nanomaterials commonly used for tumor therapy, such as peptides, liposomes, and carbon nanotubes, as well as the responses of NDDSs to pH, enzymes, magnetic fields, light, and multiple stimuli. Specifically, well-designed NDDSs can change in size or morphology or rupture when induced by one or more stimuli. The varying responses of NDDSs to stimulation contribute to the molecular design and development of novel NDDSs, providing new ideas for improving drug penetration and accumulation, inhibiting tumor resistance and metastasis, and enhancing immunotherapy.

Key processes in tumor metastasis and therapeutic strategies with nanocarriers: a review.

Cancer metastasis is the leading cause of cancer-related death. Metastasis occurs at all stages of tumor development, with unexplored changes occurring at the primary site and distant colonization sites. The growing understanding of the metastatic process of tumor cells has contributed to the emergence of better treatment options and strategies. This review summarizes a range of features related to tumor cell metastasis and nanobased drug delivery systems for inhibiting tumor metastasis. The mechanisms of tumor metastasis in the ideal order of metastatic progression were summarized. We focus on the prominent role of nanocarriers in the treatment of tumor metastasis, summarizing the latest applications of nanocarriers in combination with drugs to target important components and processes of tumor metastasis and providing ideas for more effective nanodrug delivery systems.

Impaired GPX4 activity elicits ferroptosis in alveolar type II cells promoting PHMG-induced pulmonary fibrosis development.

Inhaling polyhexamethylene guanidine (PHMG) aerosol, a broad-spectrum disinfectant, can lead to severe pulmonary fibrosis. Ferroptosis, a form of programmed cell death triggered by iron-dependent lipid peroxidation, is believed to play a role in the chemical-induced pulmonary injury. This study aimed to investigate the mechanism of ferroptosis in the progression of PHMG-induced pulmonary fibrosis. C57BL/6 J mice and the alveolar type II cell line MLE-12 were used to evaluate the toxicity of PHMG in vivo and in vitro, respectively. The findings indicated that iron deposition was observed in PHMG induced pulmonary fibrosis mouse model and ferroptosis related genes have changed after 8 weeks PHMG exposure. Additionally, there were disturbances in the antioxidant system and mitochondrial damage in MLE-12 cells following a 12-hour treatment with PHMG. Furthermore, the study observed an increase in lipid peroxidation and a decrease in GPX4 activity in MLE-12 cells after exposure to PHMG. Moreover, pretreatment with the ferroptosis inhibitors Ferrostatin-1 (Fer-1) and Liproxstatin-1 (Lip-1) not only restored the antioxidant system and GPX4 activity but also mitigated lipid peroxidation. Current data exhibit the role of ferroptosis pathway in PHMG-induced pulmonary fibrosis and provide a potential target for future treatment.

Comparative analysis of paraspinal muscle imbalance between idiopathic scoliosis and congenital scoliosis from the transcriptome aspect.

Background: Previous studies have analyzed paraspinal muscle imbalance in idiopathic scoliosis (IS) with methods including imaging, histology and electromyography. However, whether paraspinal muscle imbalance is the cause or the consequence of spinal deformities in IS remains unclear. Comparison of paraspinal muscle imbalance between IS and congenital scoliosis (CS) may shed some light on the causality of paraspinal muscle imbalance and IS. This study aimed to elucidate the generality and individuality of paraspinal muscle imbalance between IS and CS from gene expression. Methods: Five pairs of surgical-treated IS and CS patients were matched. Bilateral paraspinal muscles at the apex were collected for transcriptome sequencing. Differentially expressed genes (DEGs) between the convexity and concavity in both IS and CS were identified. Comparison of DEGs between IS and CS was conducted to discriminate IS-specific DEGs from DEGs shared by both IS and CS. Bioinformatics analysis was performed. The top 10 hub genes in the protein-protein interaction (PPI) network of IS-specific DEGs were validated by quantitative PCR (qPCR) in 10 pairs of IS and CS patients. Results: A total of 370 DEGs were identified in IS, whereas 380 DEGs were identified in CS. Comparison of DEGs between IS and CS identified 59 DEGs shared by IS and CS, along with 311 DEGs specific for IS. These IS-specific DEGs were enriched in response to external stimulus and signaling receptor binding in GO terms and calcium signaling pathway in KEGG pathways. The top 10 hub genes in the PPI network of IS-specific DEGs include BDKRB1, PRH1-TAS2R14, CNR2, NPY4R, HTR1E, CXCL3, ICAM1, ALB, ADIPOQ, and GCGR. Among these hub genes, the asymmetrical expression of PRH1-TAS2R14 and ADIPOQ in IS but not CS were validated by qPCR. Conclusions: Transcriptomic differences in bilateral paraspinal muscles between the convexity and concavity in IS share few similarities with those in CS.

Fluorescent cellulose nanofibrils-based hydrogel incorporating MIL-125-NH2 for effective adsorption and detection of iodide ion.

To remove iodine ion (I-) from wastewater, a novel hydrogel, the fluorescent cellulose nanofibrils-based hydrogel (FCNH), was synthesized to enable both detection and adsorption of I-. The FCNH comprised cellulose nanofibrils (CNs), silver nanoclusters (AgNCs), and MIL-125-NH2. It exhibited an excellent adsorption capacity for I-, with a maximum adsorption capacity of 373.7 mg/g, fitting both the Langmuir and pseudo-second-order models. Additionally, FCNH displayed excellent regeneration properties, retaining 88.0 % of its initial adsorption capacity after six adsorption-desorption cycles. Functioning as a fluorescent sensor, the synthesized FCNH enabled the detection of I- through dynamic quenching, with linear ranges of 5 to 200 mg/L and 0.2 to 1.0 µg/L, and a determination limit of 0.11 µg/L. Analysis of the adsorption and detection mechanisms revealed that FCNH's outstanding performance arose from its 3D porous structure comprising CNs, AgNCs, and MIL-125-NH2. Economic analysis indicated that FCNH was inexpensive compared to commercially available activated carbon. Thus, FCNH demonstrated significant potential as an economical and reusable adsorbent for iodine ion removal.

Chondroitin sulfate-modified antiangiogenic peptide conjugate induces cell apoptosis via the mitochondria-mediated pathway to perform antitumor activity.

Tumor growth and metastasis heavily rely on angiogenesis, crucial for solid tumor development. Inhibiting angiogenesis associated with tumors emerges as a potent therapeutic approach. Our previous work synthesized the chondroitin sulfate-modified antiangiogenic peptide CS-ES2-AF (CS-EA), which exhibited better antiangiogenic activity, longer half-life, and more robust targeting. In this work, we further evaluated the stability in vitro, cellular uptake mechanism, cell apoptosis mechanism, antitumor activity in vivo, and safety of CS-EA. The stability of CS-EA was consistently superior to that of EA at different temperatures and in different pH ranges. Furthermore, CS-EA mainly entered EAhy926 cells through the clathrin-mediated endocytosis pathway. CS-EA inhibited endothelial cell proliferation, and induced cell apoptosis through downregulating the Bcl-2, reducing mitochondria membrane potential, upregulating cytochrome c, Caspase 3, and reactive oxygen species levels. CS-EA showed better antitumor activity in the B16 xenografted tumor model, with a tumor inhibition rate 1.92 times higher than EA. Simultaneously, it was observed that CS-EA did not cause any harmful effects on the vital organs of the mice. These findings indicate that CS-EA holds significant promise for the treatment of tumors.

Feasibility of Using Intraoperative Neurophysiological Monitoring for Detecting Bone Layer of Cervical Spine Surgery.

STUDY DESIGN: Intraoperative neurophysiological monitoring (IONM) as a guide to bone layer estimation was examined during posterior cervical spine lamina grinding. OBJECTIVE: To explore the feasibility of IONM to estimate bone layer thickness. SUMMARY OF BACKGROUND DATA: Cervical laminoplasty is a classic operation for cervical spondylosis. To increase safety and accuracy, surgery-assistant robots are currently being studied. It combines the advantages of various program awareness methods to form a feasible security strategy. In the field of spinal surgery, robots have been successfully used to help place pedicle screws. IONM is used to monitor intraoperative nerve conditions in spinal surgery. This study was designed to explore the feasibility of adding IONM to robot safety strategies. METHODS: Chinese miniature pig model was used. Electrodes were placed on the lamina, and the minimum stimulation threshold of DNEP for each lamina was measured (Intact lamina, IL). The laminae were ground to measure the DNEP threshold after incomplete grinding (Inner cortical bone preserved, ICP) and complete grinding (Inner cortical bone grinded, ICG). Subsequently, the lateral cervical mass screw canal drilling was performed, and the t-EMG threshold of the intact and perforated screw canals was measured and compared. RESULT: The threshold was significantly lower than that of the recommended threshold of DENP via percutaneous cervical laminae measurement. The DNEP threshold decreases with the process of laminae grinding. The DNEP threshold of the IL group was significantly higher than ICP and ICG group, while there was no significant difference between the ICP group and the ICG group. There was no significant relationship between the integrity of the cervical spine lateral mass screw path and t-EMG threshold. CONCLUSIONS: It is feasible to use DENP threshold to estimate lamina thickness. Cervical lateral mass screw canals by t-EMG showed no help to evaluate the integrity.

Chondroitin sulfate-based universal nanoparticle delivers angiogenic inhibitor and paclitaxel to exhibit a combination of chemotherapy and anti-angiogenic therapy.

Blocking the tumor nutrient supply through angiogenic inhibitors is an effective treatment approach for malignant tumors. However, using angiogenic inhibitors alone may not be enough to achieve a significant tumor response. Therefore, we recently designed a universal drug delivery system combining chemotherapy and anti-angiogenic therapy to target tumor cells while minimizing drug-related side effects. This system (termed as PCCE) is composed of biomaterial chondroitin sulfate (CS), the anti-angiogenic peptide ES2, and paclitaxel (PTX), which collectively enhance antitumor properties. Interestingly, the PCCE system is conferred exceptional cell membrane permeability due to inherent characteristics of CS, including CD44 receptor-mediated endocytosis. The PCCE could respond to the acidic and high glutathione conditions, thereby releasing PTX and ES2. PCCE could effectively inhibit the proliferation, migration, and invasion of tumor cells and cause apoptosis, while PCCE can affect the endothelial cells tube formation and exert anti-angiogenic function. Consistently, more potent in vivo antitumor efficacy and non-toxic sides were demonstrated in B16F10 xenograft mouse models. PCCE can achieve excellent antitumor activity via modulating angiogenic and apoptosis-related factors. In summary, we have successfully developed an intelligent and responsive CS-based nanocarrier known as PCCE for delivering various antitumor drugs, offering a promising strategy for treating malignant tumors.

Methotrexate-Loaded Chitosan Oligosaccharide-ES2 for Targeted Cancer Therapy.

Cancer presents a significant health threat, necessitating the development of more precise, efficient, and less damaging treatment approaches. To address this challenge, we employed the 1-ethyl-(3-dimethyl aminopropyl) carbodiimide/N-hydroxy succinimide (EDC/NHS) catalytic system and utilized quaternized chitosan oligosaccharide (HTCOSC) as a drug carrier to construct a nanoparticle delivery system termed HTCOSC-cRGD-ES2-MTX (CREM). This system specifically targets integrin αvß3 on tumor cell surfaces and enables simultaneous loading of the antiangiogenic agent ES2 (IVRRADRAAVP) and the chemotherapy drug methotrexate (MTX). Due to its amphiphilic properties, CREM self-assembles into nanoparticles in aqueous solution, exhibiting an average diameter of 179.47 nm. Comparative studies demonstrated that CREM, in contrast to free ES2 and MTX-free nanoparticles (CRE), significantly suppressed the proliferation of EAhy926 endothelial cells and B16 melanoma cells in vitro, resulting in inhibition rates of 71.18 and 82.25%, respectively. Furthermore, CREM exhibited a hemolysis rate below 2%, indicating excellent in vitro antiangiogenic and antitumor activity as well as favorable blood compatibility. Additionally, both CRE and CREM demonstrated favorable tumor targeting capabilities through the specific binding action of cyclic RGD (cRGD) to integrin αvß3. Further in vivo investigations revealed that CREM induced apoptosis in tumor cells via the mitochondrial apoptotic pathway and reduced the expression of angiogenic factors such as vascular endothelial growth factor (VEGF), thereby inhibiting tumor angiogenesis. This potent antitumor effect was evident through a tumor suppression rate of 80.19%. Importantly, histopathological staining (HE staining) demonstrated the absence of significant toxic side effects of CREM on various organs compared to MTX. In conclusion, the CREM nano drug delivery system synergistically enhances the therapeutic efficacy of antiangiogenic drugs and chemotherapeutic agents, thus offering a novel targeted approach for cancer treatment.

Hidden blood loss in three different endoscopic spinal procedures for lumbar disc herniation.

Purpose: This study compared hidden blood loss (HBL) among three different endoscopic spinal procedures and investigated its risk factors. Patients and methods: This single-centre retrospective analysis collected data from consecutive hospitalized patients with single-segment lumbar disc herniation (LDH) undergoing unilateral biportal endoscopic discectomy (UBE), percutaneous endoscopic transforaminal discectomy (PETD), or percutaneous endoscopic interlaminar discectomy (PEID) from December 2020 to October 2022. HBL was calculated using Nadler's and Gross's formulas. The authors used Pearson's or Spearman's correlation analysis to explore the relationship between patient characteristics and HBL. Multivariate linear regression analysis was used to identify independent risk factors for HBL. Results: In total, 122 consecutive patients (68 females and 54 males) were enroled in this study. The average HBL was 381.87±218.01 ml in the UBE group, 252.05±118.44 ml in the PETD group and 229.63±143.9 ml in the PEID group (P<0.05). Pearson's or Spearman's correlation analysis showed that operative time, preoperative haemoglobin, preoperative haematocrit, and preoperative Albumin (ALB) were correlated with HBL in the UBE group, while sex, age, operative time, postoperative ALB, and patients' blood volume (PBV) were related to HBL in the PETD group (P<0.05). Operative time and preoperative activated partial thromboplastin time were related to HBL in the PEID group (P<0.05). Multiple linear regression analysis showed a positive correlation between HBL and operative time in all three groups (P<0.001, P<0.001, P<0.05). Conclusion: HBL was higher in the UBE group than in the PETD and PEID groups, and operative time may be a common risk factor for the three groups.

Isolation, purification, and antiosteoporosis activity of donkey bone collagen from discarded bone and its antioxidant peptides.

Oxidative stress plays a crucial role in the development of osteoporosis. In this study, it was observed that donkey bone collagen (DC) at a concentration of 500 µg/mL scavenged 17.89 % of 1,1-Diphenyl-2-picrylhydrazyl (DPPH) free radicals, indicating its antioxidant properties. Additionally, when an oxidative damage osteoblast model was created using H2O2, 100 µg/mL DC demonstrated the ability to enhance cell survival by 27.31 %. Furthermore, 50 µg/mL DC increased the intracellular differentiation marker alkaline phosphatase (ALP) level by 62.65 %. Additionally, the study revealed that DC significantly increased the expression of osteoporosis-related factors in serum and effectively restored the abnormal structure of spongy bone in mice osteoporosis model. Peptides (GGWFL, ANLGPA, and GWFK) isolated from DC through gastrointestinal digestion and subsequent enzymatic purification in vitro demonstrated the ability to safeguard osteoblasts from H2O2-induced damage by reducing intracellular reactive oxygen species (ROS). This protection resulted in enhanced cell survival and promoted osteoblast differentiation. This investigation underscores that DC can shield oxidative damage osteoblast model from oxidative stress, ameliorate osteoporosis, and enhance bone density in mice osteoporosis model. These findings suggest various DC applications in the food and medicine industries.

Uniportal Full-endoscopic Foraminotomy for Lumbar Foraminal Stenosis: Clinical Characteristics and Functional Outcomes.

OBJECTIVE: Uniportal full-endoscopic foraminotomy offers a promising alternative to conventional surgical methods for individuals afflicted by lumbar foraminal stenosis. This study aims to evaluate the efficacy and clinical outcomes of uniportal full-endoscopic foraminotomy in patients diagnosed with lumbar foraminal stenosis. METHODS: A comprehensive retrospective analysis was conducted on individuals who underwent full-endoscopic foraminotomy in our medical center, between January 2018 and December 2019. The investigation encompassed the demographic data of patients and key clinical metrics such as the visual analogue scale of leg (VAS-L) and back pain (VAS-B), Oswestry disability index (ODI) scores, the Short Form-36 Health Survey physical component summary (SF-36 PCS) and the mental component summary (SF-36 MCS), as well as modified MacNab grades, were systematically assessed and compared. Furthermore, radiological parameters: Coronal Cobb angle (CCA), Intervertebral angle changes (IAC), Disc height index (DHI), the foraminal cross-sectional area (FCSA) and the FCSA enlargement ratio were also compared. A variety of statistical analyses including Student t-test, chi-square tests, Fisher's exact tests, Pearson's and Spearman's correlation analyses, and Interclass Correlation Coefficients (ICCs) were employed. RESULTS: 64 patients, including 34 males and 30 females were enrolled. The mean follow-up period extended to 22.66 ± 7.05 months. Distribution by affected segments revealed 26.6% at L4-5, 67.1% at L5-S1 level, and 6.25% at both L4-L5 and L5-S1 levels. At the final follow-up, VAS-L decreased from 7.26 ± 1.19 to 1.37 ± 1.25, while VAS-B decreased from 6.95 ± 0.54 to 1.62 ± 1.13 (p < 0.001). ODI score also demonstrated a substantial decrease from 74.73 ± 8.68 to 23.27 ± 8.71 (p < 0.001). Both SF-36 PCS and SF-36 MCS scores improved significantly (p < 0.001). Modified MacNab criteria revealed 58 excellent-good patients (90.7%), and 6 fair-poor patients (9.3%). No significant differences were founded in the CCA (p = 0.1065), IAC (p = 0.5544), and DHI (p = 0.1348) between pre-operation and the final follow-up. However, the FCSA significantly increased from 73.41 ± 11.75 to 173.40 ± 18.62 mm2 (p < 0.001), and the enlargement ratio was 142.9% ± 49.58%. Notably, the final follow-up FCSA and the FCSA enlargement ratio were found to be larger in the excellent and good group compared to the fair and poor group, according to the modified MacNab criteria. CONCLUSION: The utilization of uniportal full-endoscopic foraminotomy has demonstrated its safety and efficacy in addressing lumbar foraminal stenosis. The clinical success of this procedure appears to be closely associated with the radiological decompression of the intervertebral foramen area. Importantly, the application of this technology does not seem to compromise the overall stability of the lumbar region.

High-Level Biosynthesis of Chlorogenic Acid from Mixed Carbon Sources of Xylose and Glucose through a Rationally Refactored Pathway Network.

Chlorogenic acid (CGA) has incredible potential for various pharmaceutical, nutraceutical, and agricultural applications. However, the traditional extraction approach from plants is time-consuming, further limiting its production. Herein, we design and construct the de novo biosynthesis pathway of CGA using modular coculture engineering in Escherichia coli, which is composed of MG09 and BD07 strains. To accomplish this, the phenylalanine-deficient MG09 strain was engineered to utilize xylose preferentially and to overproduce precursor caffeic acid, while the tyrosine-deficient BD07 strain was constructed to consume glucose exclusively to enhance another precursor quinic acid availability for the biosynthesis of CGA. Further pathway modularization and balancing in the context of syntrophic cocultures resulted in additional production improvement. The coculture strategy avoids metabolic flux competition in the biosynthesis of two CGA precursors, caffeic acid and quinic acid, and allows for production improvement by balancing module proportions. Finally, the optimized coculture based on the aforementioned efforts produced 131.31 ± 7.89 mg/L CGA. Overall, the modular coculture engineering strategy in this study provides a reference for constructing microbial cell factories that can efficiently biomanufacture complex natural products.

Percutaneous uniportal full-endoscopic surgery for treating symptomatic lumbar facet joint cysts under local anesthesia combined with monitored anesthesia care: a preliminary report of eight cases with at least 1 year follow-up.

Background: Lumbar facet joint cysts (FJCs) are a relatively rare clinical pathology that can result in radiculopathy or neurogenic claudication. Various treatments such as percutaneous aspiration and surgery have been reported to have good clinical outcomes. However, few clinical studies have aimed to treat symptomatic lumbar FJCs by using uniportal full-endoscopic (UFE) surgery. This study aimed to investigate the preliminary clinical outcomes of UFE surgery for the treatment of lumbar FJCs under local anesthesia combined with monitored anesthesia care (MAC). Methods: Eight patients (five males and three females) with symptomatic lumbar FJCs who underwent UFE surgery under local and MAC anesthesia were enrolled in this study between January 2018 and April 2022. The clinical characteristics, radiological features, operative information, visual analog scale (VAS) score, Oswestry disability index (ODI), and overall outcome rating based on the modified MacNab criteria were retrospectively analyzed. Results: Of the eight patients, four underwent a transforaminal approach and four underwent an interlaminar approach. Postoperatively, the mean VAS score for leg pain decreased from 6.1 before surgery to 0.6 after surgery, and the ODI decreased from 74.5% to 14.7%. All patients were followed up for more than 1 year, and the good-to-excellent rate based on the modified MacNab criteria remained 100% at the last follow-up. No complications occurred during the follow-up period. Conclusion: Lumbar FJCs can cause severe radiating leg pain and/or neurogenic claudication due to the dural sac compression and nerve roots. As an alternative treatment, UFE decompression under local and MAC anesthesia may provide effective clinical outcomes for symptomatic lumbar FJCs.